Implanted pacemakers and intracardiac cardioverter defibrillators (ICD) deliver therapy to patients suffering from various heart-diseases (Clinical Cardiac Pacing and Defibrillation, 2nd edition, Ellenbogen, Kay, Wilkoff, 2000). It is known that the cardiac output depends strongly on the left heart contraction in synchrony with the right heart (see U.S. Pat. No. 6,223,079). Congestive heart failure (CHF) is defined generally as the inability of the heart to deliver enough blood to meet the metabolic demand and it is often caused by electrical conduction defects. The overall result is a reduced blood stroke volume from the left side of the heart. For CHF patients, an installed permanent pacemaker with electrodes in 3 chambers that re-synchronize the left and right ventricles contractions provides an effective therapy, (“Device Therapy for Congestive Heart Failure”, K. Ellenbogen et al, Elsevier Inc. (USA), 2004). The resynchronization task demands exact pacing management of the heart chambers such that the overall stroke volume is maximized for a given heart rate (HR), where it is known that the key point is to bring the left ventricle to contract in synchrony with the right ventricle. The re-synchronization task is patient dependent, and for each patient the best combination of pacing time intervals that restores synchrony are changed during the normal daily activities of the patient. Accordingly, a physiologically adaptive device is disclosed in WO 2005/007075, the contents of which are incorporated herein by reference, which changes the AV delay and VV interval dynamically, responding to inputs from hemodynamic sensors thus meeting the demand for auto-programmability and auto-adjustment.
However, cardiac pacemakers cannot slow down the natural atrial rate. They can increase the atrial rate by pacing the atria with a shorter VA interval (preceding the natural sinus rate) but cannot induce a prolonged VA interval. For congestive heart failure patients, slowing down the atrial rate can be a crucial requirement. For the failing heart, increasing the atrial rate does not produce a corresponding increase in the cardiac output, which may result in the brain impelling the heart to increase the rate, with no benefit. Even worse, more unproductive stress is generated in the failing heart as a result, and the condition may deteriorate.
Li M. et al in “Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats”, Circulation. 2004; 109:120-124, American Heart Association Inc. the contents of which are incorporated herein by reference, investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction. Using an implantable miniature radio-controlled electrical stimulator, they stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure and higher maximum dp/dt of left ventricular pressure than the untreated rats.
US Patent WO 2003/099377, discloses a vagus stimulator useful for slowing down the atrial rate in a controlled manner by stimulating the vagus nerve every heart beat in response to a triggering ECG feature (P wave for example) with a variable current amplitude and frequency. The vagus stimulation puts a limit to the atrial rate as pre-programmed whenever the atrial rate goes beyond a predefined limit. U.S. Pat. No. 5,330,507, the contents of which are incorporated herein by reference, discloses a vagal stimulation device within an implanted pacemaker device for the prevention and interruption of a life threatening arrhythmias. The device has two implanted heart leads, a right atrial and a right ventricle lead, and additionally two leads for stimulating the right or left vagus nerves. The implanted device monitors the electrograms of the heart, detects the atrial rate, the ventricular rates and the ST segment variations and response in the appropriate vagus nerve stimulation.
Vagal stimulation methods are used also for other clinical purposes such as preventing epilepsy seizures and ventricular rate regulation during atrial fibrillation. Such were disclosed in “Vagus Nerve Stimulation”, by Diego Rielo, eMedicine, January 2006, the contents of which are incorporated herein by reference.
Selective atrioventricular nodal (AVN) vagal stimulation (AVN-VS) has emerged as a novel strategy for ventricular rate (VR) control in atrial fibrillation (AF). AVN-VS is delivered to the epicardial fat pad that projects parasympathetic nerve fibers to the AVN Although AVN-VS preserves the physiological ventricular activation sequence, the resulting rate is slow but irregular “Ventricular Rate Control by Selective Vagal Stimulation Is Superior to Rhythm Regularization by Atrioventricular Nodal Ablation and Pacing During Atrial Fibrillation”, Shaowei Zhuang, et al, (Circulation. 2002; 106:1853.). The authors indicate that the AVN-VS although producing a superior hemodynamic performance comparing to an ablation and pacing approach, results in irregular ventricular contractions similar to the effect of drug therapy. The negative effect is manifested in both prolonging the natural atrioventricular (AV) delay as well as causing some loss of synchrony with the underlying physiologically cardiac cycle timings identified through the irregular R-R intervals.
Tosato M., in “Heart Rate Control through Vagal Nerve Stimulation” 9th Annual Conference Of the International RES Society, September 2004, Bournemouth, UK. discloses an external closed loop system for controlling the heart rate through vagal nerve stimulation that has influence on both the sinus atrial (SA) node and the atrioventricular (AV) node. Geddes L. et al. discuss in International Patent Application publication number WO 97/36637, the physiological effect on the SA and AV nodes of vagal stimulation as follows:—“The right vagus innervates the S-A node, the atrial muscle and, to a much lesser degree, the A-V node. The left vagus nerve innervates the S-A node and atrial muscle to a lesser degree than it innervates the A-V node. It is well known to physiologists that the stimulation of the right vagus nerve predominately slows the S-A node rate and thereby reduces heart rate. Stimulation of the left vagus nerve produces some slowing of the S-A node, prolongation of A-V conduction and partial or total A-V block.”
With this asymmetrical influence of vagal stimulation on the SA and AV nodes cited above, it seems that vagal stimulation interfere with the fine correlation that exist in the cardiac cycle timings of the healthy heart where there is a known dependence of the AV delay on heart rate. Since AV synchrony is extremely important and loss of AV synchrony may be the cause of the pacemaker syndrome for example, the practicality of vagal stimulating is doubtful. It remains to be learned how the cardiac cycle timings and, for example, AV synchrony can be preserved if by stimulating the right vagii the heart rate slows down rate without affecting as much the AV node. Similarly, it remains to be learned how the left vagii can be stimulated, prolonging the AV delay without affecting the SA node and the heart rate. On the other hand if both vagii are stimulated is it known what should be the stimulation frequency or current amplitude relation between right and left vagii stimulations such that the influence on the AV node and SA node preserve the correlation between heart rate and AV delay of the healthy heart and does not cause a loss of AV synchrony for example?
Vagal stimulation is generally well tolerated but some patients experience pain, coughing, or hoarseness during stimulation. In addition, Jochen Springer in “Vagal Nerve Stimulation in Chronic Heart Failure: An Anti-inflammatory Intervention?”, Circulation. 2004; 110:e34, argues that it is increasingly appreciated that efferent vagal nerve stimulation can also directly and rapidly regulate immune responses. It would appear, based on that observation, that having a system that on the one hand benefits from vagal stimulation and on the other hand minimizes the actual usage and intensity is a favourable solution to the problematic situation.
To summarize, vagal simulation is a clinical method under investigation and in practice although some difficulties are encountered in the implementation. The present invention combines cardiac resynchronization device with a vagal stimulation for treating heart failure patients and tries to benefit from the combined action of both devices so as to reduce the atrial rate by vagal stimulation and to improve the hemodynamic performance by resynchronization. In addition, since resynchronization increases the cardiac output it is expected that the heart rate should not increase as much as observed with untreated heart failure patients and hence the need and intensity of the vagal stimulation is expected to be lower comparing to a vagal stimulation device with no CRT device, and hence the combination of the two devices present here is expected to give additional advantages on top of each device therapy alone. And finally adaptive CRT device preserve AV synchrony at all heart rates in a closed loop system according to hemodynamic sensor, and hence a drawback of vagal stimulation which is loss of cardiac cycle timings and particularly the AV synchrony due to irregular R-R intervals may be cured by the present invention combined adaptive CRT and vagal stimulation system.